Comfortable ophthalmic device and methods of its production

ABSTRACT

This invention relates to comfortable ophthalmic devices and methods of producing such devices.

RELATED APPLICATIONS

This application is a non-provisional filing of two provisionalapplications, U.S. Ser. No. 60/652,809, filed on Feb. 14, 2005 and U.S.Ser. No. 60/695,783 filed on Jun. 30, 2005.

FIELD OF THE INVENTION

This invention relates to comfortable ophthalmic devices and methods ofproducing such devices.

BACKGROUND

Contact lenses have been used commercially to improve vision since the1950s. The first contact lenses were made of hard materials. Althoughthese lenses are currently used, they are not suitable for all patientsdue to their poor initial comfort. Later developments in the field gaverise to soft contact lenses, based upon hydrogels, which are extremelypopular today. These lenses have higher oxygen permeabilities and suchare often more comfortable to wear than contact lenses made of hardmaterials. However, these new lenses are not without problems.

Contact lenses can be worn by many users for 8 hours to several days ina row without any adverse reactions such as redness, soreness, mucinbuildup and symptoms of contact lens related dry eye. However, someusers begin to develop these symptoms after only a few hours of use.Many of those contact lens wearers use rewetting solutions to alleviatediscomfort associated with these adverse reactions with some success.However the use of these solutions require that users carry extrasolutions and this can be inconvenient. For these users a morecomfortable contact lens that does not require the use of rewettingsolutions would be useful. Therefore there is a need for such contactlenses and methods of making such contact lenses. It is this need thatis met by the following invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Plot of the change in diameter of treated lenses versus control.

DETAILED DESCRIPTION OF THE INVENTION

This invention includes a method of producing ophthalmic lensescomprising, consisting essentially of, or consisting of, treating apolymerized ophthalmic lens with a wetting agent, provided that theophthalmic lens formulation does not comprise said wetting agent priorto its polymerization.

As used herein, “ophthalmic lens” refers to a device that resides in oron the eye. These devices can provide optical correction or may becosmetic. Ophthalmic lenses include but are not limited to soft contactlenses, intraocular lenses, overlay lenses, ocular inserts, and opticalinserts. The preferred lenses of the invention are soft contact lensesmade from silicone elastomers or hydrogels, which include but are notlimited to silicone hydrogels, and fluorohydrogels. Soft contact lensformulations are disclosed in U.S. Pat. No. 5,710,302, WO 9421698, EP406161, JP 2000016905, U.S. Pat. Nos. 5,998,498, 6,087,415, 5,760,100,5,776,999, 5,789,461, 5,849,811, and 5,965,631. The foregoing referencesare hereby incorporated by reference in their entirety. The particularlypreferred ophthalmic lenses of the inventions are known by the UnitedStates Approved Names of acofilcon A, alofilcon A, alphafilcon A,amifilcon A, astifilcon A, atalafilcon A, balafilcon A, bisfilcon A,bufilcon A, comfilcon, crofilcon A, cyclofilcon A, darfilcon A,deltafilcon A, deltafilcon B, dimefilcon A, drooxifilcon A, epsifilconA, esterifilcon A, etafilcon A, focofilcon A, genfilcon A, govafilcon A,hefilcon A, hefilcon B, hefilcon D, hilafilcon A, hilafilcon B,hioxifilcon B, hioxifilcon C, hixoifilcon A, hydrofilcon A, lenefilconA, licryfilcon A, licryfilcon B, lidofilcon A, lidofilcon B, lotrafilconA, lotrafilcon B, mafilcon A, mesifilcon A, methafilcon B, mipafilcon A,nelfilcon A, netrafilcon A, ocufilcon A, ocufilcon B, ocufilcon C,ocufilcon D, ocufilcon E, ofilcon A, omafilcon A, oxyfilcon A,pentafilcon A, perfilcon A, pevafilcon A, phemfilcon A, polymacon,silafilcon A, siloxyfilcon A, tefilcon A, tetrafilcon A, trifilcon A,and xylofilcon A. More particularly preferred ophthalmic lenses of theinvention are genfilcon A, lenefilcon A, comfilcon, lotrafilcon A,lotraifilcon B, and balafilcon A. The most preferred lenses includeetafilcon A, nelfilcon A, hilafilcon, and polymacon.

The term “formulation” refers to the un-polymerized mixture ofcomponents used to prepare ophthalmic lenses. These components includebut are not limited to monomers, pre-polymers, diluents, catalysts,initiators tints, UV blockers, antibacterial agents, polymerizationinhibitors, and the like. These formulations can be polymerized, bythermal, chemical, and light initiated curing techniques described inthe foregoing references as well as other references in the ophthalmiclens field. As used herein, the terms “polymerized” or “polymerization”refers to these processes. The preferred methods of polymerization arethe light initiated techniques disclosed in U.S. Pat. No. 6,822,016which is hereby incorporated by reference in its entirety.

As used herein the term “treating” refers to physical methods ofcontacting the wetting agents and the ophthalmic lens. These methodsexclude placing a drop of a solution containing wetting agent into theeye of an ophthalmic lens wearer or placing a drop of such a solutiononto an ophthalmic lens prior to insertion of that lens into the eye ofa user. Preferably treating refers to physical methods of contacting thewetting agents with the ophthalmic lenses prior to selling or otherwisedelivering the ophthalmic lenses to a patient. The ophthalmic lenses maybe treated with the wetting agent anytime after they are polymerized. Itis preferred that the polymerized ophthalmic lenses be treated withwetting agents at temperature of greater than about 50° C. For examplein some processes to manufacture contact lenses, an un-polymerized, orpartially polymerized formulation is placed between two mold halves,spincasted, or static casted and polymerized. See, U.S. Pat. Nos.4,495,313; 4,680,336; 4,889,664, 3,408.429; 3,660,545; 4,113,224; and4,197,266, all of which are incorporated by reference in their entirety.In the case of hydrogels, the ophthalmic lens formulation is a hardeneddisc that is subjected to a number of different processing stepsincluding treating the polymerized ophthalmic lens with liquids (such aswater, inorganic salts, or organic solutions) to swell, or otherwiseequilibrate this polymerized ophthalmic lens prior to enclosing thepolymerized ophthalmic lens in its final packaging. Polymerizedophthalmic lenses that have not been swelled or otherwise equilibratedare known as un-hydrated polymerized ophthalmic lenses. The addition ofthe wetting agent to any of the liquids of this “swelling or“equilibrating” step at room temperature or below is considered“treating” the lenses with wetting agents as contemplated by thisinvention. In addition, the polymerized un-hydrated ophthalmic lensesmay be heated above room temperature with the wetting agent duringswelling or equilibrating steps. The preferred temperature range is fromabout 50° C. for about 15 minutes to about sterilization conditions asdescribed below, more preferably from about 50° C. to about 85° C. forabout 5 minutes.

Yet another method of treating is physically contacting polymerizedophthalmic lens (either hydrated or un-hydrated) with a wetting agent atbetween about room temperature and about 85° C. for about 1 minute toabout 72 hours, preferably about 24 to about 72 hours, followed byphysically contacting the polymerized ophthalmic lens with a wettingagent at between about 85° C. and 150° C. for about 15 minutes to aboutone hour.

Many ophthalmic lenses are packaged in individual blister packages, andsealed prior to dispensing the lenses to users. As used herein, thesepolymerized lenses are referred to as “hydrated polymerized ophthalmiclenses”. Examples of blister packages and sterilization techniques aredisclosed in the following references which are hereby incorporated byreference in their entirety, U.S. Pat. Nos. D435,966 S; 4,691,820;5,467,868; 5,704,468; 5,823,327; 6,050,398, 5,696,686; 6,018,931;5,577,367; and 5,488,815. This portion of the manufacturing processpresents another method of treating the ophthalmic lenses with wettingagents, namely adding wetting agents to packaging solution prior tosealing the package, and subsequently sterilizing the package. This isthe preferred method of treating ophthalmic lenses with wetting agents.

Sterilization can take place at different temperatures and periods oftime. The preferred sterilization conditions range from about 100° C.for about 8 hours to about 150° C. for about 0.5 minute. More preferredsterilization conditions range from about 115° C. for about 2.5 hours toabout 130° C. for about 5.0 minutes. The most preferred sterilizationconditions are about 124° C. for about 30 minutes.

The “packaging solutions” that are used in methods of this invention maybe water-based solutions. Typical packaging solutions include, withoutlimitation, saline solutions, other buffered solutions, and deionizedwater. The preferred aqueous solution is deioinized water or salinesolution containing salts including, without limitation, sodiumchloride, sodium borate, sodium phosphate, sodium hydrogenphosphate,sodium dihydrogenphosphate, or the corresponding potassium salts of thesame. These ingredients are generally combined to form bufferedsolutions that include an acid and its conjugate base, so that additionof acids and bases cause only a relatively small change in pH. Thebuffered solutions may additionally include2-(N-morpholino)ethanesulfonic acid (MES), sodium hydroxide,2,2-bis(hydroxymethyl)-2,2′,2″-nitrilotriethanol,n-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, citric acid,sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid,sodium acetate, ethylenediamine tetraacetic acid and the like andcombinations thereof. Preferably, the packaging solution is a boratebuffered or phosphate buffered saline solution or deionized water. Theparticularly preferred packaging solution contains about 1,850 ppm toabout 18,500 ppm sodium borate, most particularly preferred about 3,700ppm of sodium borate.

As used here, the term “wetting agent” refers polymers having a numberaverage molecular weight of about at least 500, that impart a moistfeeling when added to the eyes of contact lens wearers. Examples ofpreferred wetting agents include but are not limited topoly(meth)acrylamides [i.e.poly N,N-dimethylacrylamide), poly(N-methylacrylamide) poly (acrylamide),poly(N-2-hydroxyethylmethacrylamide), and poly(glucosamineacrylamide)],poly(itaconic acid), hyaluronic acid, xanthan gum, gum Arabic (acacia),starch, polymers of hydroxylalkyl(meth)acrylates [i.e.poly(2-hydroxyethylmethacrylate), poly(2,3-dihydroxypropylmethacrylate,and poly(2-hydroxyethylacrylate)], and polyvinylpyrrolidone.

Additional preferred wetting agents include but are not limited toco-polymers and graft co-polymers of the aforementioned preferredwetting agents, such co-polymers and graft co-polymers include repeatingunits of hydrophilic or hydrophobic monomers, preferably in amounts ofabout less than ten percent by weight, more preferably less than abouttwo percent. Such repeating units of hydrophilic or hydrophobic monomersinclude but are not limited to alkenes, styrenes, cyclic N-vinyl amides,acrylamides, hydroxyalkyl (meth) acrylates, alkyl (meth) acrylates,siloxane substituted acrylates, and siloxane substituted methacrylates.Specific examples of hydrophilic or hydrophobic monomers which may beused to form the above co-polymers and graft co-polymers include but arenot limited to ethylene, styrene, N-vinylpyrrolidone,N,N-dimethylacrylamide, 2-hydroxyethylmethyacrylate, methyl methacrylateand butyl methacrylate, methacryloxypropyl tristrimethylsiloxysilane andthe like. The preferred repeating units of hydrophilic or hydrophobicmonomers are N-vinylpyrrolidone, N,N-dimethylacrylamide,2-hydroxyethylmethacrylate, methyl methacrylate, and mixtures thereof.Further examples of wetting agents include but are not limited topolymers with carbon backbones and pendant polyethylene glycol chains[i.e. polymers of polyethylene glycol monoomethacrylate] copolymers ofethylene glycol [copolymers with 1,2,propyleneglycol, 1,3-propyleneglycol, methyleneglycol, and tetramethylene glycol]. The preferredwetting agents are polyvinylpyrrolidone, graft co-polymers andco-polymers of polyvinylpyrrolidone, the particularly preferred wettingagent is polyvinylpyrrolidone. Polyvinylpyrrolidone (“PVP”) is thepolymerization product of N-vinylpyrrolidone. PVP is available in avariety of molecular weights from about 500 to about 6,000,000 Daltons.These molecular weights can be expressed in term of K-values, based onkinematic viscosity measurements as described in Encyclopedia of PolymerScience and Engineering, John Wiley & Sons Inc, and will be expressed inthese numbers throughout this application. The use of PVP having thefollowing K-values from about K-30 to about K-120 is contemplated bythis invention. The more preferred K-values are about K-60 to aboutK-100, most preferably about K-80 to about K-100. For the treatment ofetafilcon A lenses, the particularly preferred K-value of PVP is aboutK-80 to about K-95, more preferably about K-85 to about K-95, mostpreferably about K-90.

The wetting agents can be added to the packaging solution at a varietyof different concentrations such as about 100 ppm to about 150,000 ppm.For example if the wetting agents are added to packaging solutionscontaining un-hydrated polymerized ophthalmic lenses, the wetting agentsare preferably present at a concentration of about 30,000 ppm to about150,000 ppm. If the wetting agents are added to packaging solutionscontaining hydrated polymerized ophthalmic lenses, the wetting agentsare preferably present at a concentration of about 100 ppm, to about3000 ppm, more preferably about 200 ppm to about 1000 ppm, mostpreferably less than about 500 ppm. For example when etafilcon A lensesare used in this invention and the wetting agent is K-90 PVP, thepreferred packaging solution concentration of PVP K-90 is about 250 ppmto about 2,500 ppm, more preferably about 300 to about 500 ppm, mostpreferably about 350 to about 440 ppm.

When etafilcon A contact lenses are heated with K-90 PVP at atemperature greater than about 120° C. for about 30 minutes at aconcentration of about 400 to about 500 ppm, the treated lenses are morecomfortable to users than untreated lenses. Further, this particularmolecular weight and concentration of PVP does not distort or shift thediameter of the lenses during the treatment cycle or distort the usersvision. While not wishing to be bound by any particular mechanism ofincorporation, it is known that K-90 PVP is incorporated into the matrixof the lens after it is treated with K-90 PVP. In an etafilcon A contactlens, the preferred amount of incorporated K-90 PVP is about 0.01 mg toabout 1.0 mg, more preferred about 0.10 mg to about 0.30 mg, mostparticularly preferred about 0.10 mg to about 0.20 mg. Lenses that havebeen treated in this manner are worn by users for up to 12 hours stillmaintain the incorporated PVP.

Further the invention includes an ocular device comprising, consistingessentially of, or consisting of a polymerized ophthalmic lens whereinsaid polymerized ophthalmic lens is treated with a wetting agent,provided that the ophthalmic lens formulation does not comprise saidwetting agent prior to its polymerization. The terms “ophthalmic lens,”“wetting agent,” “polymerized,” and “formulation” all have theiraforementioned meanings and preferred ranges. The term “treated” has theequivalent meaning and preferred ranges as the term treating.

Still further the invention includes an ocular device prepared bytreating a polymerized ophthalmic lens with a wetting agent, providedthat the ophthalmic lens formulation does not comprise said wettingagent prior to its polymerization. The terms “ophthalmic lens,” “wettingagent,” “polymerized,” “treated” and “formulation” all have theiraforementioned meanings and preferred ranges.

The application of the invention is described in further detail by useof the following examples. These examples are not meant to limit theinvention, only to illustrate its use. Other modifications that areconsidered to be within the scope of the invention, and will be apparentto those of the appropriate skill level in view of the foregoing textand following examples.

EXAMPLES Example 1

Cured etafilcon A contact lenses (sold as 1-Day Acuvue® brand contactlenses by Johnson & Johnson Vision Care, Inc.) were equilibrated indeionized water, and packaged in solutions containing PVP in boratebuffered saline solution ((1000 mL, sodium chloride 3.55 g, sodiumborate 1.85 g, boric acid 9.26 g, and ethylenediamine tetraacetic acid0.1 g: 5 rinses over 24 hours, 950±μL), sealed with a foil lid stock,and sterilized (121° C., 30 minutes). Before the addition of PVP eachsolution contained water, 1000 mL, sodium chloride 3.55 g, sodium borate1.85 g, boric acid, 9.26 g, and ethylenediamine tetraacetic acid 0.1 g.A variety of different weights and concentrations of PVP were used asshown in Table 1, below

The amount of PVP that is incorporated into each lens is determined byremoving the lenses from the packaging solution and extracting them witha mixture 1:1 mixture of N,N-dimethylforamide, (DMF) and deionized water(Dl). The extracts are evaluated by high performance liquidchromatography (HPLC). Three lenses were used for each evaluation. Theresults and their standard deviation are presented in Table 1.

TABLE 1 mg of PVP Sample # Type of PVP Conc. (ppm) in lens Control NoneNone none 1 K-12 3000 0.24 (0.01) 2 K-12 20,000 1.02 (0.01) 3 K-30 15001.39 (0.05) 4 K-30 2000 1.50 (0.01) 5 K-60 1000 0.56 (0.00) 6 K-60 15000.85 (0.02) 7 K-60 2500 1.02 (0.03) 8 K-90 250 0.10 (0.00) 9 K-90 5000.14 (0.00) 10 K-90 1000 0.2 (0.01) 11 K-90 2500 0.25 (0.02) 12 K-120500 0.07 (0.00)

Example 2

Samples of treated etafilcon A lenses were prepared via the treatmentand sterilization methods of Example 1 from K-12, K-30, K-60, K-90, andK-120 PVP at concentrations of 0.30%, 1.65%, and 3.00%. Aftersterilization, the diameter of the lenses was, compared to an untreatedlens and evaluated to determine if the process changed those diameters.The results, FIG. 1, plot the change in diameter vs the type of PVP at aparticular concentration. This data shows that K-12, K-90, and K-120have a minimal effect on the diameter of the lenses.

Example 3

Several etafilcon A lenses were treated with K-90 PVP at a concentrationof 500 ppm and sterilized according to the methods of Example 1. Thelenses were stored in their packages for approximately 28 days at roomtemperature and were then measured for diameter, base curve, spherepower, and center thickness. Thereafter, lenses were heated at 55° C.for one month. The diameter, base curve, sphere power, and centerthickness of the lenses was measured and the results were evaluatedagainst an untreated lens and data is presented in Table 2. This dataillustrates that the parameters of lenses treated with K-90 PVP are notsignificantly affected by time at elevated temperature.

TABLE 2 Change from Baseline of Sample after one month storage atBaseline 55° C. Diameter (mm) 14.37 (0.02)  0.02 Base curve (mm) 8.90(0.03) −0.01 Power (diopter) −0.75 (0.05)  0.00 Center Thickness (mm)0.127 (0.005) 0.002

Example 4

Etafilcon-A lenses treated with PVP K-90 at a concentration of 440 ppmand sterilized (124° C., approximately 18 minutes) were sampled frommanufacturing lines and measured for diameter, base curve, sphere power,and center thickness and compared to similar measurements made onuntreated 1-Day Acuvue® brand lenses. The data presented in Table 3illustrates that K-90 PVP does not significantly affect theseparameters.

TABLE 3 Treated Untreated Diameter (mm) 14.24 (0.04) 14.18 (0.04) Basecurve (mm)  8.94 (0.03)  8.94 (0.04) Sphere Power Deviation −0.01 (0.04)−0.02 (0.04) from Target (diopter) Center Thickness Deviation  0.000(0.004)  0.002 (0.005) from Target (mm)

Example 5

Etafilcon A lenses were prepared according to Example 1 at theconcentrations of Table 1. The treated lenses were clinically evaluatedin a double-masked studies of between 9 and 50 patients. The patientswore the lenses in both eyes for 3-4 days with overnight removal anddaily replacement, and wore untreated 1-Day Acuvue® brand contact lensesfor 3-4 days with overnight removal and daily replacement as a control.Patients were not allowed to use rewetting drops with either type oflens. Patients were asked to rate the lens using a questionnaire. Allpatients were asked a series of questions relating to overallpreference, comfort preference, end of day preference, and dryness. Intheir answers they were asked to distinguish if they preferred thetreated lens, the 1-Day control lens, both lenses or neither lens. Theresults are shown in Tables 4 and 5. The numbers in the columnsrepresent the percentage of patients that positively responded to eachof the four options. The “n” number represents the number of patientsfor a particular sample type. “DNT” means did not test and n/a means nonapplicable. The numbers illustrate that lenses treated with K-90 PVP ata concentration of about 500 ppm have good clinical comfort on the eye.The sample # refers to the sample numbers in Table 1.

TABLE 4 Overall Preference, % Comfort Preference, % Sample # n PVPtreated 1-Day Both Neither PVP treated 1-Day Both Neither 1 9 67 22 11 067 22 11 0 2 37 27 49 22 3 30 46 19 5 3 41 34 49 15 2 27 56 12 5 4 10 3020 50 0 30 40 30 0 5 41 27 61 10 2 22 49 29 0 6 42 33 33 33 0 33 29 38 07 37 51 27 19 3 49 11 38 3 8 41 27 37 32 5 24 34 37 5 9 48 33 27 40 0 3323 44 0 10 45 18 27 51 4 16 20 58 7

TABLE 5 Dryness Preference % End of Day Preference % Sample # n PVPtreated 1-Day Both Neither PVP treated 1-Day Both Neither 1 9 33 33 11 056 22 44 0 2 37 24 43 22 8 27 43 27 5 3 41 32 51 17 2 29 49 17 2 4 10 2040 30 10 20 10 60 10 5 41 20 46 32 2 20 41 37 2 6 31 42 24 38 0 38 35 166 7 42 36 19 38 3 41 24 40 0 8 41 27 22 49 7 22 24 41 7 9 48 38 21 46 033 19 44 0 10 45 24 20 58 4 18 20 51 4

Example 6

An etafilcon A contact lens was treated with 500 ppm of K-90 PVP usingthe methods of Example 1. The treated lenses were briefly rinsed withphosphate buffered saline solution and rinsed lenses were placed in thewell of a cell culture cluster container (Cellgrow XL) that mimics thedimensions of a human eye. See, Farris R L, Tear Analysis in ContactLens Wears, Tr. Am. Opth. Soc. Vol. LXXXIII, 1985. Four hundredmicroliters of phosphate buffered saline solution (KH₂PO₄ 0.20 g/L, KCl0.20 g/L, NaCl 8.0 g/L, Na₂HPO₄ [anhydrous] 1.15 g/L) was added to eachcontainer. The wells were covered and the container was stored in anoven at 35° C.

Three lenses were removed from the oven at various times and analyzed byHPLC to determine whether PVP was released into the phosphate bufferedsaline solution. The average results are presented in Table 6. The limitof quantification for PVP is 20 ppm. The test did not detect any PVP inthe analyzed samples. This data shows that PVP is not released at levelsgreater than 20 ppm.

TABLE 6 Time PVP Released 30 min. <20 ppm 1 hr. <20 ppm 2 hr. <20 ppm 4hr. <20 ppm 8 hr. <20 ppm 16 hr. <20 ppm 24 hr <20 ppm

1-47. (canceled)
 48. An ocular device comprising a polymerizedophthalmic lens wherein said polymerized ophthalmic lens is treatedafter polymerization but prior to hydration with a polymeric wettingagent, provided that the ophthalmic lens does not comprise saidpolymeric wetting agent prior to its polymerization.
 49. The device ofclaim 48 wherein the wetting agent is selected from the group consistingof poly(meth)acrylamides, poly(itaconic acid), hyaluronic acid, xanthangum, gum Arabic, starch, polymers of hydroxylalkyl(meth)acrylates, andpolyvinylpyrrolidone.
 50. The device of claim 48 wherein the wettingagent is polyvinylpyrrolidone, graft co-polymers ofpolyvinylpyrrolidone, and co-polymers of polyvinylpyrrolidone.
 51. Thedevice of claim 48 wherein the wetting agent is polyvinylpyrrolidone.52. The device of claim 48 comprising about 0.01 mg to about 1.0 mgpolyvinylpyrrolidone.
 53. The device of claim 48 comprising about 0.10mg to about 0.44 mg of polyvinylpyrrolidone.
 54. The device of claim 48wherein said device does not distort the user's vision.
 55. The deviceof claim 48 comprising about 0.01 mg to about 1.0 mg of a wetting agentselected from the group consisting of poly(meth)acrylamides,poly(itaconic acid), hyaluronic acid, xanthan gum, gum Arabic, starch,polymers of hydroxylalkyl(meth)acrylates, and polyvinylpyrrolidone. 56.The device of claim 48 comprising about 0.10 mg to about 0.44 mg ofpoly(meth)acrylamides, poly(itaconic acid), hyaluronic acid, xanthangum, gum Arabic, starch, polymers of hydroxylalkyl(meth)acrylates, andpolyvinylpyrrolidone.
 57. The device of claim 48 wherein said devicedoes not distort the user's vision.
 58. The device of claim 48 whereinsaid wetting agent remains in the ophthalmic lens after about 6 hours toabout 24 hours of wear by a user. 59-65. (canceled)